Tetra Discovery Partners is the recipient of an NIH Blueprint Neurotherapeutics Network award to develop phosphodiesterase-4D (PDE4D) Negative Allosteric Modulators (NAMs) for treating memory loss in patients affected by psychiatric and neurologic diseases. The Tetra-NIH Blueprint drug is projected to reach human Phase I clinical trials in late 2015. Through a Cooperative Research and Development Agreement (CRADA) with Dr Robert Innis and Dr Victor Pike of the NIMH Intramural Program, the company has been working in parallel to develop novel PET ligands for imaging PDE4 subtypes in the human brain. The goal of the proposed Phase I SBIR is to develop a PDE4D PET ligand useful for assessing target occupancy in human Phase I clinical trials of the Tetra-NIH Blueprint drug as well as a PET ligand that will be useful for assessing PDE4D levels in patients with psychiatric and neurologic disease. PDE4D as a target for improving cognition in humans has genetic validation through studies of children with PDE4D gene mutations who develop an ultra-rare disorder known as acrodysostosis type-2 (ACRDY2; MIM 600129). ACRDY2 is a developmental disorder characterized by intellectual disability, brachydactyly, nasal hypoplasia and short stature. Children with acrodysostosis only achieve an IQ of 50-80. Thus, PDE4D is the human ortholog of the Drosophila PDE4 gene in which the Dunce mutation was the first learning mutation identified in a model organism. Rolipram and other PDE4 inhibitors have been shown to be broadly pro-cognitive in numerous animal models of learning and memory, while knock-out or knock-down of the mouse PDE4D gene also improves learning and memory. Our NIMH collaborators, Innis and Pike, have shown that PDE4 PET imaging is altered in patients with major depression. Those studies used C-11 (R)-rolipram as a PET ligand for assessing PDE4 levels, however, rolipram binds equally to the different subtypes of PDE4 expressed in brain (PDE4A, PDE4B & PDE4D). We therefore want to understand if PDE4D levels are altered in major depression and other psychiatric diseases. In the Phase I SBIR, Tetra will optimize potent and selective PDE4D NAMs for C-11 or F-18 labelling by Innis and Pike who will conduct in vivo PET imaging studies. Should a suitable PDE4D PET ligand be identified, the imaging agent could rapidly advance into human clinical trials.